Psoriasis presents a unique opportunity to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. Findings in psoriasis of Treg dysfunction in combination with high IL-6 levels and the capacity of this cytokine to inhibit regulatory T cell function and stimulate Th17 differentiation may explain observed alterations in psoriatic T cell response. Based upon our observations that a) IL-6 is produced at high levels in critical T cell microenvironments in psoriatic skin, b) that IL-6 can inhibit suppression of effector cell proliferation by human T regulatory cells, and c) that psoriatic T cells exhibit hyper-responsive phosphorylation of STAT3, it is critical to test whether IL-6 and and/or other STAT3-activating cytokines favor escape for Tmem/eff cells from suppression. Thus we will I.) Determine whether the psoriatic lesional milieu can create functionally decreased psoriatic Treg activity via effector T cells becoming refractive to suppression by psoriatic regulatory T cells. On the Treg side, our published and preliminary data demonstrate that psoriatic Tregs are functionally less effective, are insufficient numerically to functionally suppress in developed psoriatic lesions, have decreased numbers of CCR5+ Tregs, decreased chemotaxis to Rantes and Mip1a, decreased CD73, and increased IFI27 (ISG12). Furthermore, over-expressed psoriatic STAT3-associated signaling cytokines such as IL-6, IL-23, and IL-22, in combination with IL- 1 and TGFb, can divert the differentiation of Tregs from precursors away from a regulatory phenotype and toward a pathogenic Th17 cell pathway, or even cause trans-differentiative re-programming of committed Tregs into IFNg-, IL-17-,or TNF-producing Teff cells. Therefore, we will also II.) Determine whether the psoriatic lesional milieu can a) induce the abnormal profile of psoriatic Treg cells, b) divert differentiation away from Treg development toward Th17's, or c) cause trans-differentiative re-programming of Tregs into Teff cells. Designing a model that recapitulates the effector/regulatory T cells changes observed in psoriasis will allow for high throughput analysis of potential therapeutic reagents and opens new research opportunities in diseases where regulatory T cells play a role. PUBLIC HEALTH RELEVANCE: The current application proposes to dissect the interplay between protective regulatory T cells, and pathogenic Th1 and Th17 type T cells. A more comprehensive understanding of the relationship between regulatory and pathogenic effector T cells in psoriasis is necessary to gain insight into the mechanism(s) of action for drugs already in use for psoriasis, Crohn's and rheumatoid/psoriatic arthritis. Better understanding of the mechanisms for efficacious therapies will help to improve the next generation of therapeutics and identify more tailored targets for intervention.